The respiratory tract, like other mucosal surfaces, is protected by a multifaceted immune system from exposure to pathogenic microorganisms, environmental particulates, and allergens. Remarkably, the normal distal respiratory epithelial surface is free of chronic inflammation, a situation that optimizes gas exchange across the alveolar membrane. The collectin proteins (collagen-like lectins) are components of the multifaceted innate response in the blood and at most mucosal surfaces of the body. Two collectins, surfactant protein A (SP-A) and surfactant protein D (SP-D), are secreted by respiratory epithelial cells into the lining fluids of the respiratory tract, in good position to modulate the immune response. In this proposal, we will focus on the role of SP-D in host defense against influenza virus and address a possibly novel role for SP-D in modulating the acquired immune response to viral infection. We will also test the hypothesis that variations in collectin quaternary structure, specifically variability in self-association of SP-D trimers into higher-order multimers, modulates the function of SP-D in defense against influenza. We further hypothesize that substitution of a threonine for a methionine at position 11 in human SP-D due to a common SNP is a genetic determinant of SP-D multimer formation. Our study design is based on the truism that structure begets function. We will first characterize the biochemical basis for SP-D multimer formation and the altered quaternary structures caused by the Met^11Thr-encoding SNP (aim 1). We will then study the role of SP-D, and its variant haplotypes, in antigen presentation and the acquired cellular response to influenza in vitro and in vivo (aims 2 and 3).